Fructosamine Testing for Glycemic Control: When and Why to Order Fructosamine Tests and How to Interpret the Results
Author: Emilia Kapcia, PharmD Candidate 2025, Northeastern University School of Pharmacy
Reviewer: Courtney Cameron, PharmD, BCACP
What are HbA1c and fructosamine tests in diabetes?
Diabetes Mellitus (DM) is a chronic condition characterized by high blood glucose. Diabetes causes significant morbidity, disability, and premature mortality through microvascular and macrovascular complications, which can be delayed and even prevented by achieving and maintaining glycemic control.1
Fructosamine and hemoglobin A1c (HbA1c) are two tests to measure blood glucose levels in diabetes. HbA1c is predominantly considered the gold standard measure for the diagnosis and the evaluation of DM. HbA1c is produced via binding of glucose and hemoglobin, as shown in Figure 1a.2 Because erythrocytes are typically renewed every 90 days, HbA1c gives a reflection of the blood glucose over the preceding 2 to 3 months.3 Fructosamine on the other hand is a non-enzymatic glycated protein that is formed when blood glucose binds to serum proteins, predominantly albumin. Albumin serves as a surrogate measure of the total protein content that glucose binds within the blood serum, as shown in Figure 1b.4 Because of the shorter lifespan of albumin, it reflects the average glucose levels over just 2 to 3 weeks.5
Figure 1 (a) and (b):
When would HbA1c become unreliable in determining glycemic control?
Although HbA1c is a good diabetes diagnostic tool and prognostic marker of complications, there are some limitations to its measure. The value of HbA1c can be affected by hemoglobinopathy, the degree of erythropoiesis, altered erythrocyte turnover, erythrocyte destruction, physiologic changes, and glycation.6 Therefore, certain medical conditions, particularly those influenced by hemoglobin metabolism, may result in HbA1c levels that are unreliable for determining glycemic control in diabetes.5 Some examples of these conditions include pregnancy, chronic kidney disease (CKD) or end-stage renal disease (ESRD), blood disorders like sickle cell or hemolytic anemia, patients on hemodialysis, and patients with alcohol use disorder, amongst others.2 In pregnancy, a physiological drop in hemoglobin causes increased red blood cell turnover and increased plasma volume leading to a lower HbA1c.6,7 In kidney disease, there is decreased erythropoietin (EPO) production, causing the red blood cell count to drop and anemia develops. With anemia, decreased red blood cell turnover exposes the cell to glucose for a longer period of time, resulting in higher HbA1c values.8 Therefore, in conditions like these, non-traditional, alternative glycemic biomarkers, like fructosamine, may have a role in glycemic monitoring.
Why would fructosamine be used over HbA1c?
Due to how it is formed, fructosamine is affected by changes in serum protein metabolism, particularly albumin, and is not impacted by alterations in erythrocyte turnover.9 Therefore, fructosamine is not influenced by hemoglobin levels and may be a more useful measure of blood sugar control than HbA1c in conditions characterized by shortened erythrocyte lifespan such as pregnancy, hemoglobinopathies, chronic kidney failure, and other blood disorders.10 Additionally, due to fructosamine reflecting glucose concentration over 2-3 weeks, this biomarker serves as a clinically advantageous measure when there is a need to respond more quickly to changes in therapy.11 Moreover, if home blood sugar readings are unable to be captured, fructosamine tests can enable providers to make appropriate treatment decisions and modifications sooner, especially in the conditions where stricter glycemic control is crucial.
How are fructosamine levels interpreted and how do they correlate to HbA1c?
The reference range of fructosamine is around 200-285 mmol/L, therefore levels above 285 mmol/L typically indicate increased blood sugar.12 For individuals with uncontrolled glycemic control in diabetes, the fructosamine range is elevated up to 268-870 mmol/L.8 High fructosamine levels indicate that high average glucose concentrations occurred in the preceding 2 to 3 weeks. If elevated, the test should be repeated and if again elevated, indicates poor glucose control.8
One study modeled the discordance between HbA1c and fructosamine based on a group of 153 patients with a mean age of 47 years, of which 46% had type 1 diabetes and 47% type 2 diabetes.13 A plot of measured HbA1c values was compared to measured fructosamine levels. From this, a regression line was extrapolated and determined to be HbA1C = 0.017 x Fructosamine + 1.61, with a correlation coefficient, or r value, of 0.78 as shown in Figure 2.13 As a reminder, the correlation coefficient measures the strength of association of a relationship between two variables. The r value ranges from -1 and 1, indicating either a negative or positive correlation respectively, and with a value of 0 indicating no linear relationship. The closer the r value is to -1 or 1, the stronger the relationship. In this case, the variables being associated are fructosamine to HbA1c. An r value of 0.78 is suggestive of a strong positive correlation between these two variables.
From this, study investigators correlated a set of HbA1c and fructosamine values, see Table 1. A fructosamine value of 285 mmol/L, the upper limit of the reference range, correlates to a HbA1c of 6.5%, the HbA1c value that is diagnostic of diabetes.14 This demonstrates the concordance between HbA1c and fructosamine, providing an indication of how to interpret fructosamine test results and relate them to a well-known measure of glycemic control like HbA1c.
Figure 2:
Table 1:
What are the drawbacks and consideration of the fructosamine test?
Sometimes, the reliability of the fructosamine test can be compromised. Any condition that significantly influences serum albumin production and metabolism, may in turn affect the reliability of fructosamine testing.15 In particular, the blood levels of fructosamine may be altered in nephrotic syndrome, liver disease (ie, hepatic cirrhosis), and thyroid disease.15 Another disadvantage of fructosamine is that its concentration is influenced by levels of immunoglobulins, particularly IgA, which are present in conditions like Celiac disease and Berger disease.15 In addition, high levels of ascorbic acid can interfere with the reliability of the test and patients need to abstain from vitamin C supplements for 24 hours prior.
Summary
In summary, it is critical to consider the importance of alternative non-traditional glycemic biomarkers like fructosamine in cases where HbA1c may be unreliable. Fructosamine is a marker that reflects blood glucose levels over a shorter period compared to HbA1c. It is particularly useful in situations where conditions affecting hemoglobin metabolism may interfere with the accuracy of HbA1c levels. By utilizing measures like fructosamine, providers can improve diabetic monitoring and better manage glycemic control in patients with diabetes, especially in patient populations where HbA1c may not provide an accurate representation of glycemic status, like those who are pregnant, have CKD, ESRD, on hemodialysis, anemia, and other hemoglobinopathies.
References:
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